Description of Research Expertise

Description of Research
Research in the Doms lab utilizes a wide array of cell biological, biochemical, genetic, and immunological techniques to study membrane proteins important in HIV/AIDS pathogenesis as well as relatively new research projects on Rift Valley Fever virus and other members of the bunyavirus family in which we seek to identify host cell pathways that are used by these viruses to infect cells.

In order for HIV-1 to enter a cell, the viral Env protein must bind to CD4, the primary virus receptor. However, CD4 binding alone is not sufficient to trigger the conformational changes in Env that lead to membrane fusion and virus entry. For this to occur, the virus must also interact with the appropriate coreceptor. We found that macrophage-tropic virus strains, which are involved in transmission and are the predominant virus type isolated from infected individuals, require the chemokine receptor CCR5 in addition to CD4 for infection to occur. The importance of CCR5 in vivo was shown by our finding that approximately 1% of Caucasian individuals lack CCR5; these individuals are extraordinarily resistant to HIV-1 infection. Over time, T-cell tropic virus strains emerge in some infected individuals; these viruses typically require the chemokine receptor CXCR4 in conjunction with CD4. The discovery of HIV-1 specific coreceptors has important implications for understanding viral tropism pathogenesis, and for the development of novel anti-viral agents.

Current projects involve the use of specific inhibitors of virus entry, many of which are now used clinically including the membrane fusion inhibitor enfuvirtide and the CCR5 antagonist maraviroc. By studying the entry process, we hope to characterize why some virus strains are more sensitive to certain classes of entry inhibitors than other virus strains and to determine if these differences correlate with virus tropism or pathogenesis. This information could also be used to help guide clinical therapy. A great deal of our work in this area involves examining viruses obtained from patients who have received these drugs, as we attempt to identify how HIV acquires resistance to entry inhibitors, and the implications this has for viral tropism. Finally, now that the structure of the HIV Env protein is better understood and the receptors with which it interacts have been identified, it is now possible to rationally modify the Env protein through genetic means in the hopes of eliciting more effective immunogens. We use both HIV-1, HIV-2 and SIV systems to address these points, comparing closely related virus strains that differ markedly in their pathogenic potential to understand how specific structural alterations can impact virus replication in vivo. Our work in this area is supported by the International AIDS Vaccine Initiative.

Over the past several years, we have initiated projects Rift Valley fever virus and several other bunyaviruses that cause disease in humans. This work is being done in collaboration with colleagues at USAMRIID at Ft. Detrick, MD as well as the Centers for Disease Control. Cell biological and genetic studies are being done at Penn, while BSL4 work is done at USAMRIID. One of our students is now a postdoctoral fellow at Ft. Detrick. We are generally interested in how these viruses interact with host cells, and in identifying host pathways that are utilized by viruses during their life cycle. Much of this work is being done in collaboration with Dr. Sara Cherry, who is an expert in applying high throughput RNAi screens to the study of different viruses.

Members of the Doms lab

Current members of the Doms lab, with the month and the year they joined the lab, their previous institution, and a brief description of their projects (updated summer 2008):

Postdocs:

Meg Laakso (2/06) Ph.D. Baylor College of Medicine. HIV vaccine development and genetic modification of the viral Env protein

Chip Tilton (4/06) M.D. Yale University School of Medicine and NIH. Evolution of the humoral immune response to HIV in the face of entry inhibitor therapy; in vivo resistance of HIV to CCR5 inhibitors